Using the technique of intracerebral injection of drug via permanently implanted fine-gauge (30-gauge) cannulae, we have been mapping the rat brain to find CNS sites which mediate morphine analgesia. So far, we have identified two sites, (1) the posterior hypothalamus, and (2) the periaqueductal gray, which mediate morphine analgesia. Morphine microinjections in the latter site, in addition to yielding significant analgesia, also resulted in an explosive hyperreactivity to auditory and visual stimuli which were previously neutral stimuli. Such paradoxical effects have never before been observed with systemic administrations of morphine. Two-way analgesic cross tolerance was obtained between systemic (i.p.) and intracerebral (i.c.) injections in the periaqueductal gray (PAG). When rats were pretreated with i.p. morphine, then given a test dose of i.c. morphine in the PAG, these rats showed analgesic tolerance as compared to saline-pretreated controls. Conversely, when rats were pretreated with i.c. morphine, then given a test dose of i.p. morphine at 20 mg/kg, these rats showed analgesic tolerance as compared to a control group given the vehicle alone (Ringer's only without the morphine) in the PAG, or a group given morphine in a non-analgesic site (i.e., substantia nigra). These results indicating 2-way analgesic cross tolerance between the PAG morphine microinjections and systemic morphine injections point definitively to the PAG as an important site of morphine analgesia.